The accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) induces a coordinated adaptive program called the unfolded protein response (UPR). The UPR alleviates stress by upregulating protein folding and degradation pathways in the ER and inhibiting protein synthesis. With a basic conceptual framework for the UPR, including the identification of key mediators of the response, now in place, recent work has turned towards investigating how the response is regulated and how its effects radiate beyond the immediate realm of protein secretion. This review highlights advances in these areas and attempts to forecast important issues that must be addressed soon.